Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Can Mediate Degradation of the Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1)

Abstract

Elevated LDL-cholesterol (LDLc) levels are a major risk factor for cardiovascular disease and atherosclerosis. LDLc is cleared from circulation by the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR in endosomes/lysosomes, resulting in increased circulating LDLc. PCSK9 can also mediate the degradation of LDLR lacking its cytosolic tail, suggesting the presence of as yet undefined lysosomal-targeting factor(s). Herein, we confirm this, and also eliminate a role for the transmembrane-domain of the LDLR in mediating its PCSK9-induced internalization and degradation. Recent findings from our laboratory also suggest a role for PCSK9 in enhancing tumor metastasis. We show herein that while the LDLR is insensitive to PCSK9 in murine B16F1 melanoma cells, PCSK9 is able to induce degradation of the low density lipoprotein receptor-related protein 1 (LRP-1), suggesting distinct targeting mechanisms for these receptors. Furthermore, PCSK9 is still capable of acting upon the LDLR in CHO 13-5-1 cells lacking LRP-1. Conversely, PCSK9 also acts on LRP-1 in the absence of the LDLR in CHO-A7 cells, where re-introduction of the LDLR leads to reduced PCSK9-mediated degradation of LRP-1. Thus, while PCSK9 is capable of inducing degradation of LRP-1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP-1 for PCSK9 activity. Identification of PCSK9 targets should allow a better understanding of the consequences of PCSK9 inhibition for lowering LDLc and tumor metastasis.

PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role

“…The association of Lp(a) with HepG2 cells was increased when LDLR expression was increased and decreased when LDLR expression was reduced. PCSK9 has been shown to interact with and modulate the expression of other lipoprotein/lipid receptors in addition to LDLR under certain conditions (35)(36)(37)(38)(39). Reports have described a role for some of these receptors in cellular uptake of Lp(a), although in our study PCSK9 was not found to modify expression of other lipoprotein receptors, providing further support for this proposed mechanism of Lp(a) clearance being LDLR mediated (40,41).…”

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

“…They found that aortic cholesterol levels were reduced, without observing effects on lesion area in the aortic root or thoracic aorta of other LDLR family members, such as LDLR related protein 1 (LRP1), that could also bind and clear lipoproteins (63)(64)(65)(66)(67)(68) …”

Lipoprotein(a) and inhibitors of proprotein convertase subtilisin/kexin type 9

“…While there are very few studies on the interaction between LRP-1 and PCSK9, a recent in vivo experimental study on melanoma and CHO cells has shown that PCSK9 can induce the degradation of LRP-1 (24), suggesting that Lp(a) reduction by PCSK9 inhibitors may be mediated via the LRP-1 pathway.…”